EP0212400B1 - Méthode de préparation de dérivés de la sphingosine - Google Patents

Méthode de préparation de dérivés de la sphingosine Download PDF

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EP0212400B1
EP0212400B1 EP86110694A EP86110694A EP0212400B1 EP 0212400 B1 EP0212400 B1 EP 0212400B1 EP 86110694 A EP86110694 A EP 86110694A EP 86110694 A EP86110694 A EP 86110694A EP 0212400 B1 EP0212400 B1 EP 0212400B1
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EP0212400A2 (fr
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Richard R. Prof. Dr. Schmidt
Peter Zimmermann
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ICN Switzerland AG
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Solco Basel AG
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H15/00—Compounds containing hydrocarbon or substituted hydrocarbon radicals directly attached to hetero atoms of saccharide radicals
    • C07H15/02—Acyclic radicals, not substituted by cyclic structures
    • C07H15/04—Acyclic radicals, not substituted by cyclic structures attached to an oxygen atom of the saccharide radical
    • C07H15/10—Acyclic radicals, not substituted by cyclic structures attached to an oxygen atom of the saccharide radical containing unsaturated carbon-to-carbon bonds
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
    • Y02P20/00—Technologies relating to chemical industry
    • Y02P20/50—Improvements relating to the production of bulk chemicals
    • Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

Definitions

  • European patent application no. 84114415.7 (publication no. 146 810) relates to new sphingosine derivatives of the formulas: and methods of making them.
  • R1 is the acyl radical of a fatty acid having 14 to 24 carbon atoms or the corresponding acyl radicals having a hydroxyl group in the ⁇ -position or having one or two double bonds in the cis configuration
  • R2 is the pentadecanyl or heptadecanyl radical or the corresponding C15 and C17 Residues with one, two or three double bonds, one of which sits in the 1,2 position and has a trans configuration, the other or other, if present, have a cis configuration.
  • These compounds have the erythro configuration and correspond to the already known neutral glycosphingolipids. They are characterized by wound healing or cell and tissue-regenerating properties and are suitable for therapeutic use in wounds of any genesis, especially in poorly or slowly healing wounds or ulcerations. Indeed, especially when applied topically to wounds, they lead to the formation of healthy, well-perfused new tissue without annoying scars.
  • the sphingosine derivatives of the formula (I) -D are preferred because of their higher therapeutic activity.
  • the production of the above-mentioned compounds is based on corresponding ceramides of the formulas: out.
  • the ceramides in turn can be prepared from the C18- or C20-sphingosines by N-acylation using a fatty acid of the formula R1-OH.
  • the compounds of the formula (I) -D or (I) -L are obtained in optically uniform form or else a mixture of the diastereomers (I) -D and ( I) -L; in the latter case, the diastereomers must be separated at a certain process stage.
  • racemic sphingosines can now be obtained with good yield from glycine by simple synthesis by RR Schmidt and R. thorough [Angew. Chem. 94 , 215-216 (1982); Appl. Chem. Int. Ed. Engl. 21 , 210-211 (1982); Appl. Chem. Suppl. 1982 , 393 - 397] can be obtained.
  • the production process discussed above also provides the sphingosine derivatives of the formula (I) -D or (I) -L with a satisfactory yield, a process which does not require the separation of diastereomers should be preferred - especially when one considers that the more effective compounds belong to the D series.
  • R1 represents the same acyl radicals as given above in the discussion of formulas (I) -D and (I) -L, while R3 is an aliphatic radical having 13 to 19 carbon atoms, of which at least 13 are in a straight chain and optionally at most 4 are present as lateral methyl groups, which radical can contain up to three double bonds of cis or trans configuration or up to three triple bonds.
  • the process according to the invention consists of D-galactose with a lower aliphatic ketone or an aromatic aldehyde of the formula R-CO-R ', in which R and R' each represent a lower alkyl radical or one of R and R 'is the hydrogen atom and the other represents an aromatic radical, converted to a D-galactose of the formula (II) protected in the 4- and 6-positions, this compound with an oxidizing agent which cleaves vicinal diols to the corresponding D protected in the 2- and 4-positions -Threose of formula (III) splits, the protected D-threose with an R3-CH2-phosphonate or an R3-CH2-triphenylphosphonium halide, in which R3 has the above meaning, in the presence of a base or a base and a salt too soon Reacts compound of formula (IV), in this compound converts the free hydroxyl group into an azido group by activation, the resulting azid
  • the organic carboxylic acid R1-OH from which the acyl group R1 in the sphingosine derivatives of the formula (I) is derived, is for example the myristic acid C14H28O2, the palmitic acid C16H32O2, the stearic acid C18H36O2, the oleic acid C1 CH34O22, the linoleic acid C18 Behenic acid C22H44O2 and - at the upper limit of the meaning given for R1 - the tetracosanoic acid (lignoceric acid) C24H48O2, the cis-15-tetracosenoic acid (nervonic acid) C24H46O2, the 2-hydroxy-tetracosanoic acid (cerebronic acid) C24H48O3 15, the 2-hydroxy tetracosenoic acid (hydroxynervonic acid) C24H46O3 or the isomeric 2-hydroxy-17-tetracosenoic acid with the latter.
  • the aliphatic radical R3 can be an unbranched chain or carry one, two, three or four methyl groups as substituents. Furthermore, the chain can be saturated or unsaturated; in the latter case it has one to three double bonds or one to three triple bonds. The double bonds have the cis or the trans configuration.
  • Preferred aliphatic radicals R3 are those with an odd number of carbon atoms, especially the C13 and C15 radicals.
  • a lower aliphatic ketone such as acetone, ethyl methyl ketone or diethyl ketone, or an aldehyde of the aromatic series such as benzaldehyde or a benzaldehyde substituted on the phenyl ring can be used to protect the hydroxyl groups in the 4- and 6-position of the D-galactose.
  • benzaldehyde is preferred for this purpose.
  • Suitable condensation agents for the reaction are generally Lewis acids, such as zinc chloride, boron trifluoride, aluminum chloride and iron chloride, or Br ⁇ nsted acids, such as p-toluenesulfonic acid.
  • the conversion of D-galactose into 4,6-O-benzylidene-D-galactose can be carried out, for example, according to the method of EG Gros and V. Deulofeu [J. Org. Chem. 29 , 3647-3654 (1964)], the conversion of D-galactose with acetone to 4,6-O-isopropylidene-D-galactose can be carried out according to the method of J. Gelas and D. Horton [Carbohydr. Res. 71 , 103-121 (1979)].
  • the oxidizing agent used in the second stage of the process may be an alkali metal periodate, e.g. the lithium, sodium or potassium salt, or lead tetraacetate; sodium periodate is preferably used.
  • the oxidation is advantageously carried out at a pH around 7 to 8, e.g. in an appropriate buffer solution, and carried out at room temperature.
  • the Wittig reaction according to the third stage of the process is usually in an inert gas atmosphere, for example under nitrogen, at low temperatures, for example at -10 to -20 ° C, and when using an R3-CH2-phosphonium halide in the presence of a salt, for example lithium bromide , Sodium chloride or potassium bromide.
  • Suitable bases include organic lithium compounds, in particular phenyllithium or lithium methylate, also sodium amide, sodium methylate and sodium carbonate.
  • Aromatic hydrocarbons such as benzene, toluene or xylene, or ethers such as diethyl ether, tetrahydrofuran or dioxane can be used as solvents; the solvent should be anhydrous.
  • the conversion of the free hydroxyl group into an azido group by activation can advantageously be carried out by 0-sulfonation of the compound (IV) and subsequent reaction of the 0-sulfonyl derivative formed, for example the methanesulfonyl, trifluoromethanesulfonyl or p-toluenesulfonyl derivative, with an alkali metal azide; this involves an inversion of the configuration at C2 of the D-threose.
  • the O-sulfonation can be carried out according to the methods described in "Ullmanns Encyklopadie der Technische Chemie", 4th edition, volume 11, pages 91 and following, Verlag Chemie GmbH, Weinheim BRD (1976).
  • An acid halide or an acid anhydride of a lower aliphatic sulfonic acid or a monocyclic aromatic sulfonic acid for example methanesulfonyl chloride, p-toluenesulfonyl chloride, methanesulfonic acid anhydride or trifluoromethanesulfonic acid anhydride, is generally used.
  • the 0-sulfonation is preferably carried out in the presence of a base.
  • the base is particularly suitable as tertiary organic bases such as triethylamine, dimethylaniline, pyridine, collidine, lutidine and the like.
  • the subsequent reaction with the alkali metal azide, for example lithium, sodium or potassium azide, is advantageously carried out without purifying the O-sulfonyl derivative. Both reactions are preferably carried out in an inert gas atmosphere, for example under nitrogen, and at low temperatures or room temperature.
  • the protective group can be split off from the compound (V) by acidic hydrolysis.
  • the compound is dissolved in an organic solvent such as dichloromethane or dimethylformanide and then a small amount of concentrated hydrochloric acid and water are allowed to act for a while, preferably at room temperature.
  • the compound (VI) can be subjected to glycosidation directly to form a compound (VII) or can be converted via the intermediates (VIII), (IX) and (X) into a compound (XI) which is only subjected to glycosidation .
  • this second process variant comprises three reaction stages more, it gives a higher overall yield and is therefore particularly well suited for production on an industrial scale. It is explained in more detail below.
  • the primary hydroxyl group of the 2-azido-1,3-dihydroxy compound (VI) should be protected with reagents which react selectively with the former in the presence of a primary and a secondary hydroxyl group.
  • Particularly suitable as protective group R ′′ are those which have a high spatial stress, such as the tert-butyl, triphenylmethyl (trityl), trichloroacetyl, trimethylsilyl, tert.butyldimethylsilyl or tert.butyldiphenylsilyl group.
  • the triphenylmethyl, monomethoxytriphenylmethyl, tert.butyldimethylsilyl and tert.butyldiphenylsilyl group are preferred.
  • the protective group R '' is introduced using the known methods of organic chemistry, depending on the type of protective group chosen.
  • the triphenylmethyl group can be introduced by treating the compound (VI) with an appropriate halide such as the triphenylchloromethane or the triphenylbromomethane.
  • the corresponding halide preferably the chloride or the bromide, can also be used advantageously for the tert-butyldimethylsilyl and the tert-butyldiphenylsilyl group.
  • the 1-position protected compound of formula (VIII) on the 3-position hydroxyl group is then protected by a protecting group R '' ', e.g. by esterification with an organic carboxylic acid Ac'OH or a reactive functional derivative thereof.
  • a protecting group R '' ' e.g. by esterification with an organic carboxylic acid Ac'OH or a reactive functional derivative thereof.
  • simple, aliphatic carboxylic acids and aromatic, in particular monocyclic, aromatic carboxylic acids are suitable for this purpose; preference is given to using benzoic acid, a substituted benzoic acid or pivalic acid.
  • the esterification with the carboxylic acid Ac'OH can be carried out according to the methods described in "Ullmanns Encyklopedia of Industrial Chemistry", 4th edition, volume 11, pages 91 and following, Verlag Chemie GmbH, Weinheim BRD (1976). It is advantageously carried out using a carboxylic acid halide in the presence of a tertiary organic base such as triethylamine, pyridine or dimethylaniline, in an anhydrous organic solvent such as benzene, toluene, tetrahydrofuran, diethyl ether or dichloromethane.
  • a tertiary organic base such as triethylamine, pyridine or dimethylaniline
  • an anhydrous organic solvent such as benzene, toluene, tetrahydrofuran, diethyl ether or dichloromethane.
  • the protective group R ′′ of the hydroxyl group in the 1-position of the compound of the formula (IX) can be eliminated by acid hydrolysis (triphenylmethyl protecting groups, silyl protecting groups) or by treatment with boron trifluoride etherate (triphenylmethyl groups).
  • reaction of the compound (IX) or that of the compound (VI) with the O-trichloro- or O-trifluoroacetimidate of D-glucose, the hydroxyl groups of which are protected by acyl radicals Ac, apart from that at the 1-position, is advantageous catalyzed by a Lewis acid such as boron trifluoride etherate or trimethylsilyl trifluoromethanesulfonate. It is generally carried out in an anhydrous organic solvent such as a hydrocarbon (hexane) or a halogenated hydrocarbon (dichloromethane).
  • Lower aliphatic acyl groups such as the acetyl, propionyl, pivaloyl, trifluoroacetyl or methanesulfonyl group are preferably used as acyl radicals for protecting the hydroxyl groups in the 2-, 3-, 4- and 6-positions of D-glucose. Details on the preparation of the reagent can be found in the paper by RR Schmidt and M. Stumpp (Liebigs Ann. Chem. 1983 , 1249-1256) and RR Schmidt, J. Michel and M. Roos (Liebigs Ann. Chem. 1984 , 1343-1357 ) can be removed.
  • the corresponding reaction with the 1-halogen derivative of O-tetraacylated D-glucose is generally carried out in the presence of a heavy metal compound such as silver oxide, a heavy metal salt, such as silver carbonate or mercury cyanide, or an organic base, which act as acid-binding agents, carried out (Ullmanns Encyklopadie der technical chemistry, 4th edition, volume 24, page 757, Verlag Chemie GmbH, Weinheim BRD 1983).
  • the cleavage of the acyl radicals Ac and the protective group R '''from the compound (VII) or (XI) is generally catalyzed by bases;
  • the use of sodium methoxide in anhydrous methanol at room temperature is particularly expedient for this.
  • the conversion of the azido group into the primary amino group is best accomplished by treating the compound (XII) with hydrogen sulfide at room temperature.
  • the compound is dissolved, for example, in a mixture (1: 1) of water and pyridine.
  • the same transfer can also be carried out by hydrogenation with sodium borohydride or another reducing agent, e.g. Sodium cyanoborohydride.
  • the N-acylation of the compound (XIII) with the organic carboxylic acid of the formula R1-OH can be carried out by the method of D. Shapiro and co-workers [J. At the. Chem. Soc. 86 , 4472 (1964)].
  • the carboxylic acid will be used even in the presence of a dehydrating agent such as dicyclohexylcarbodiimide in dichloromethane, or a functional reactive derivative of the carboxylic acid such as an activated ester or a halide in the presence of an inorganic base such as sodium acetate or a tertiary organic base.
  • the N-acylation is advantageously carried out at room temperature.
  • the melting points given were determined on a copper block and are not corrected.
  • Preparative column chromatography was carried out using silica gel 60 (0.062-0.200 mm) from Merck. Ready-made columns according to D. Flockerzi, diploma thesis, University of Stuttgartt / FRG (1978) with silica gel "LiChroprep Si 60.15-25" were used for the medium pressure chromatography.
  • compound (4) has been subjected to the same treatment with hydrogen sulfide (see below) as described in section (h) of the previous example.
  • the compound (5) has been obtained, the physicochemical properties of which completely match those of the erythro-D-C18 sphingosine prepared from natural sources.

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Claims (12)

  1. Procédé de préparation de dérivés de sphingosine de formule générale (I)
    Figure imgb0007
     dans laquelle R¹ représente le radical acyle d'un acide gras comportant de 14 à 24 atomes de carbone ou le radical acyle correspondant portant un groupe hydroxyle en position α ou portant une ou deux doubles liaisons de configuration cis et R³ représente un radical aliphatique comportant de 13 à 19 atomes de carbone dont 13 au moins se trouvent en chaîne droite et dont, cas échéant, 4 au plus se trouvent sous forme de groupes méthyliques latéraux, ce radical pouvant comporter jusqu'à trois doubles liaisons de configuration cis ou trans ou jusqu'à trois triples liaisons, caractérisé en ce que l'on fait réagir le D-galactose avec une cétone aliphatique inférieure ou un aldéhyde aromatique de formule R-CO-R', dans laquelle R et R' représentent chacun un radical alcoyle inférieur ou bien l'un de R et R' représente un atome d'hydrogène et l'autre représente un radical aromatique, pour obtenir un D-galactose protégé en les positions 4 et 6, de formule (II), on scinde ce composé au moyen d'un agent d'oxydation capable de scinder les diols vicinaux, pour obtenir un D-thréose protégé en les positions 2 et 4, de formule (III), on fait réagir le D-thréose protégé avec un R³-CH₂-phosphonate ou un halogénure de R³-CH₂-triphénylphosphonium, dans lesquels R³ a la signification indiquée ci-dessus, en présence d'une base ou d'une base et d'un sel, pour obtenir un composé de formule (IV), on transforme le groupe hydroxyle libre de ce composé, par activation, en un groupe azido, on libère le composé azido obtenu, de formule (V) des groupes protecteurs des groupes hydroxyle en les positions 1 et 3 de la chaîne aliphatique avec formation d'un composé 2-azido-1,3-dihydroxy de formule (VI), on fait réagir ce dernier avec un réactif organique qui est capable de réagir de manière sélective avec un groupe hydroxyle primaire, avec formation d'un composé de formule (VIII), dans laquelle R'' représente le groupe protecteur d'un hydroxyle, on bloque le groupe hydroxyle secondaire dans le composé de formule (VIII) au moyen d'un groupe protecteur R''', on scinde du composé obtenu de formule (IX) le groupe protecteur de l'hydroxyle R'', avec formation d'un composé de formule (X) et, au moyen du 0-trifluor- ou 0-trichlor-acétimidate ou du dérivé 1-halogéné d'un D-glucose dont les groupes hydroxyle en les positions 2, 3, 4 et 6 sont protégés par des radicaux acyle, on transforme en un composé glucosilé de formule (VII) ou (XI) soit le composé obtenu précédemment de formule (VI), soit au contraire le composé de formule (X), on scinde du composé obtenu les groupes acyle Ac ou les groupes acyle Ac et le groupe protecteur R''' avec formation d'un même composé de formule (XII), on transforme le groupe azido de celui-ci en un groupe amino primaire et on soumet le composé obtenu de formule (XIII) à une N-acylation au moyen d'un acide gras de formule R¹-OH.
  2. Procédé selon la revendication 1, caractérisé en ce que l'on utilise, comme cétone ou aldéhyde de formule R-CO-R', l'acétone, l'éthylméthylcétone ou la diéthylcétone, ou bien le benzaldéhyde ou un benzaldéhyde substitué sur le cycle phénylique.
  3. Procédé selon la revendication 1, caractérisé en ce que l'on utilise comme agent d'oxydation un periodate de métal alcalin ou le tétraacétate de plomb et que l'oxydation du composé de formule (II) est effectuée à un pH d'environ 7 ou 8, à la température ordinaire.
  4. Procédé selon la revendication 1, caractérisé en ce que la réaction du D-thréose protégé de formule (III) avec le R³-CH₂-phosphonate ou l'halogénure de R³-CH₂-triphénylphosphonium est effectuée en présence de phényllithium, de méthylate de lithium, d'amidure de sodium, de méthylate de sodium ou de carbonate de sodium, dans un hydrocarbure ou un éther anhydre, sous atmosphère d'azote, à basses températures et, lorsqu'on emploie un halogénure de R³-CH₂-phosphonium, avec addition d'un sel.
  5. Procédé selon la revendication 1, caractérisé en ce que la transformation du groupe hydroxyle libre du composé de formule (IV) en un groupe azido est effectuée par une O-trifluorméthanesulfonation, méthanesulfonation ou p-toluènesulfonation et réaction subséquente du dérivé O-sulfonyle avec un azidure de métal alcalin.
  6. Procédé selon la revendication 1, caractérisé en ce que la scission du groupe protecteur R-CO-R' du composé de formule (V) ou du groupe protecteur R'' du composé de formule (IX) est effectuée par hydrolyse acide.
  7. Procédé selon la revendication 1, caractérisé en ce que l'on emploie, comme groupe protecteur de l'hydroxyle R'', un groupe volumineux tel que le groupe triphénylméthyle, monométhoxytriphénylméthyle, tert.butyle, trichloracétyle, triméthyl-, tert.butyldiméthylsilyle ou tert.butyldiphénylsilyle.
  8. Procédé selon la revendication 1, caractérisé en ce que l'on emploie comme groupe protecteur R''' le radical acyle d'un acide carbonique aliphatique ou aromatique ou un groupe tert. butoxycarbonyle, de préférence le radical acyle de l'acide benzoïque ou d'un acide benzoïque substituté ou de l'acide pivalique.
  9. Procédé selon la revendication 1, caractérisé en ce que la transformation du composé de formule (VI) ou (X) en un glucoside est effectuée avec ledit O-trifluor- ou O-trichlor-acétimidate en présence d'un catalyseur acide de Lewis et dans un hydrocarbure ou un hydrocarbure halogéné anhydre, la réaction avec ledit dérivé 1-halogéné, en présence d'un agent de liaison des acides ou d'un sel de métal lourd.
  10. Procédé selon la revendication 1, caractérisé en ce que l'on scinde les groupes acyle Ac et le groupe protecteur R''' du composé de formule (VII) ou (IX) par catalyse basique.
  11. Procédé selon la revendication 1, caractérisé en ce que l'on effectue la transformation du groupe azido du composé de formule (XII) en un groupe amino primaire par traitement avec de l'hydrogène sulfuré dans un mélange d'eau et de pyridine (1 : 1) ou par hydrogénation au moyen de borohydrure de sodium ou d'un autre agent réducteur.
  12. Procédé selon la revendication 1, caractérisé en ce que l'on effectue la N-acylation du composé de formule (XIII) au moyen de l'acide gras de formule R¹-OH en présence d'un agent d'élimination de l'eau ou au moyen d'un ester activé de l'acide gras ou au moyen d'un halogénure de celui-ci en présence d'une base minérale ou d'une base organique tertiaire.
EP86110694A 1985-08-13 1986-08-02 Méthode de préparation de dérivés de la sphingosine Expired - Lifetime EP0212400B1 (fr)

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AT86110694T ATE71104T1 (de) 1985-08-13 1986-08-02 Neues verfahren zur herstellung von sphingosinderivaten.

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DE3819870A1 (de) * 1987-06-12 1988-12-29 Hoerrmann Wilhelm Arzneimittel auf der basis von fett-amino-alkoholen
IT1235162B (it) * 1988-12-02 1992-06-22 Fidia Farmaceutici Derivati di lisosfingolipidi
FR2673179B1 (fr) * 1991-02-21 1993-06-11 Oreal Ceramides, leur procede de preparation et leurs applications en cosmetique et en dermopharmacie.
GB9207182D0 (en) * 1992-04-01 1992-05-13 Enzymatix Ltd Glycolipids and their preparation
WO1994009020A1 (fr) * 1992-10-22 1994-04-28 Kirin Beer Kabushiki Kaisha Nouveau shingoglycolipide et son utilisation
WO1995003028A1 (fr) * 1993-07-23 1995-02-02 Morris Herstein Composition cosmetique stimulant le renouvellement de la peau, avec effet prolonge d'elimination de l'irritation
ES2117304T3 (es) * 1993-10-18 1998-08-01 Virginia Tech Intell Prop Sintesis de esfingosinas.
US5663151A (en) * 1994-03-04 1997-09-02 Bristol-Myers Squibb Company Sulfated α-glycolipid derivatives as cell adhesion inhibitors
CA2142153A1 (fr) * 1994-03-04 1995-09-05 Jacques Banville Derives .beta.-glycolipidiques sulfates, inhibiteurs de l'adherence cellulaire
US5686426A (en) * 1994-11-17 1997-11-11 Bristol-Myers Squibb Company Dicarboxymethylated glycolipid derivatives as cell adhesion inhibitors
EP0994888B1 (fr) 1998-05-14 2004-02-04 Cosmoferm B.V. Procede d'acylation d'amino-alcools
WO2000068238A1 (fr) * 1999-05-10 2000-11-16 Lipiderm Ltd. Procede de preparation a grande echelle de sphingosines et de ceramides
US7156661B2 (en) * 2002-08-22 2007-01-02 Align Technology, Inc. Systems and methods for treatment analysis by teeth matching

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* Cited by examiner, † Cited by third party
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FR2478104B1 (fr) * 1980-03-17 1986-08-08 Merieux Inst Nouveaux derives de gangliosides, leur preparation et leur application
EP0146810A3 (fr) * 1983-12-05 1987-05-13 Solco Basel AG Procédé de préparation de dérivés de la sphingosine

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PL149578B1 (en) 1990-02-28
ATE71104T1 (de) 1992-01-15
FI863272A (fi) 1987-02-14
DK165984B (da) 1993-02-22
DE3683214D1 (de) 1992-02-13
AU603773B2 (en) 1990-11-29
DK382486D0 (da) 1986-08-11
EP0212400A2 (fr) 1987-03-04
HU197916B (en) 1989-06-28
US4937328A (en) 1990-06-26
FI863272A0 (fi) 1986-08-12
NO163453C (no) 1990-05-30
AR242395A1 (es) 1993-03-31
DK165984C (da) 1993-07-19
FI82058C (fi) 1991-01-10
HUT42500A (en) 1987-07-28
AU6108386A (en) 1987-02-19
PL261011A1 (en) 1987-06-01
DK382486A (da) 1987-02-14
EP0212400A3 (en) 1987-10-28
NO863251L (no) 1987-02-16
CA1267891A (fr) 1990-04-17
ES2001208A6 (es) 1988-05-01
YU142886A (en) 1988-06-30
FI82058B (fi) 1990-09-28
NO863251D0 (no) 1986-08-12
NO163453B (no) 1990-02-19

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